Investigating Long-Term Antibody, B Cell, and T Cell Immunity in Ebola Survivors Using a Longitudinal Biobank

Ebolavirus disease (EVD) is characterised by severe symptoms, including extreme fever and multi-organ failure, which often necessitate hospitalisation and can lead to high mortality rates. The largest recorded outbreak of EVD occurred a decade ago and had a profound global impact, especially on the West African nations of Guinea, Sierra Leone, and Liberia. Since the 2013-2016 epidemic, there has been a heightened research focus on understanding the long-term immune response to Ebolavirus (EBOV) infection. One critical insight emerging from these studies is that EBOV can persist in immune-privileged sites within the body-such as the central nervous system, eyes, and reproductive organs-long after initial infection. This persistence allows for a possible re-emergence and transmission of the virus to others through bodily fluids, such as breast milk and semen, months or even years post-recovery. These findings underscore the importance of ongoing research into the chronic and infectious nature of EBOV in survivors. A recent hypothesis suggests that EVD survivors experience a unique "decay-stimulation-decay" pattern in their antibody response. This pattern could be due to intermittent re-exposure of the immune system to EBOV antigens over time, potentially, as a result of viral reservoirs located in immune privileged sites within the body. Our proposed research aims to test this hypothesis by exploring whether a large cohort of EVD survivors experience a periodic re-stimulation of their EBOV specific immune response and if EBOV antigen can be detected in longitudinally matched plasma samples. Results from this research will add to our fundamental understanding of the adaptive immune response following natural EBOV infection. This research will use a unique biobank developed in collaboration with EVD survivor groups in Guinea. This biobank comprises matched longitudinal samples of plasma and peripheral blood mononuclear cells (PBMCs) collected between 2015 - 2024. These samples are a critical resource, providing a rare opportunity to track the evolution of B and T cell responses over extended periods in the same individual. I aim to delineate how the antibody and cellular immune responses to EBOV are maintained and mature years after the primary infection, focusing on parameters such as antibody affinity, B cell receptor diversity, and memory B and T cell phenotype. The objectives of this fellowship are threefold: (1) To characterise the pattern of EBOV-specific antibody decay in survivors, (2) to identify the role of viral antigen persistence in modulating this response, and (3) to assess the cellular immune response dynamics and memory phenotype specific to EVD. The knowledge generated by this research could help inform on strategies to monitor and manage the risks posed by sexual transmission of EBOV, which remains a public health concern. This knowledge could inform on protocols to limit potential outbreaks originating from survivors and improve risk assessment and health guidelines for long-term survivors. This work thus holds potential applications for EBOV outbreak prevention and control, public health policy, and vaccine optimisation and policy, marking an important step forward in addressing the global health challenges posed by EBOV and other viral pathogens with similar latent or chronic immune-evading characteristics.